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Thursday, 25 December 2014

Dilantin, 5,5-Diphenylhydantoin, Phenytoin

Phenytoin3DanJ.gif





Phenytoin2DCSD.svg



Phenytoin sodium, Dilantin, is a commonly used antiepileptic. Phenytoin acts to suppress the abnormal brain activity seen in seizure by reducing electrical conductance among brain cells by stabilizing the inactive state of voltage-gated sodium channels. Aside from seizures, it is an option in the treatment of trigeminal neuralgia in the event that carbamazepine or other first-line treatment seems inappropriate.



It is sometimes considered a class 1b antiarrhythmic.



Phenytoin, 5,5-diphenylimidazolidinedione is synthesized in two different ways. The first involves a base catalyzed addition of urea to benzil followed by a benzilic acid rearrangement (1,2 phenyl migration) to form the desired product. This is known as the Biltz Synthesis of phenytoin. 

Phenytoin2DCSD.svg

Systematic (IUPAC) name
5,5-diphenylimidazolidine-2,4-dione
Clinical data
Trade namesDilantin
AHFS/Drugs.commonograph
MedlinePlusa682022
Pregnancy cat.
Legal status
RoutesOral, parenteral
Pharmacokinetic data
Bioavailability70-100% oral, 24.4% for rectal and intravenous administration
Protein binding90%
Metabolismhepatic
Half-life6–24 hours
ExcretionPrimarily through the bile, urinary
Identifiers
CAS number57-41-0 Yes
ATC codeN03AB02
PubChemCID 1775
DrugBankDB00252
ChemSpider1710 Yes
UNII6158TKW0C5 Yes
KEGGD00512 Yes
ChEBICHEBI:8107 
ChEMBLCHEMBL16 
Chemical data
FormulaC15H12N2O2 
Mol. mass252.268 g/mol


Dilantin (phenytoin sodium injection, USP) is a ready-mixed solution of phenytoin sodium in a vehicle containing 40% propylene glycol and 10% alcohol in water for injection, adjusted to pH 12 with sodium hydroxide. Phenytoin sodium is related to the barbiturates in chemical structure, but has a five-membered ring. The chemical name is sodium 5,5-diphenyl-2, 4-imidazolidinedione represented by the following structural formula:
Dilantin® (Phenytoin Sodium) Structural Formula Illustration



 Step by step to synthesis Dilantin



The synthesis processes of 5,5-diphenylhydantion are as follows:







The processes could be divided into three steps:


1.      Preparation of Benzoin 



2.      Preparation of Benzil 



3.      Preparation of 5,5-diphenylhydantion 















STEP 1

ImagesHandler.ashx?logoNoURL=1&id=8093&w=150&h=150&.png


  • Molecular formula: C14H12O2
  • Molar mass: 212.244
  • CAS Registry Number: Not available
  • Appearance: Benzoin, 99%; Benzoin, 99%; white to light yellow crystals with a faint, sweet, balsamic odour; light yellow powder or crystals with a camphor-like odour
  • Melting point: 134 to 136 °C
  • Boiling point: Not available
  • Solubility: Water, 300 mg/L (25 deg C), 300 mg/L (25 deg C)
  • Safety sheet: Not available
  • Spectra: ChemSpider (1H NMR13C NMR), NMRShiftDB 13C NMR, also check on SDBS.

Benzoin is the precursor of the antiepileptic medicine, Dilantin (Phenytoin).

Benzoin is also a white crystal perfumery. The DL-type is a hexagon monoclinic rhombic crystal. Both D-type and L-type are needle-shape crystals.



In this experiment, a benzoin condensation of benzaldehyde is carried out with a biological coenzyme, thiamine hydrochloride, as the catalyst.




Reaction equation






Vitamin B1 is a coenzyme. It may replace the extremely toxic substance, sodium cyanide, as the catalyst, is benzoin condensation. The structure of Vitamin B1 is as fallow:





Mechanism


Step 1



Step 2



Step 3





BenzoinNMRforSM.PNG - 4kB







Chemical


1.      Vitamin Bhydrochloride: 1.20g


2.      Benzaldehyde: ~6.24g




3.      Ethanol 95%: 12mL

4.      Sodium hydroxide solution: 2.5M 4.0mL



Procedure


1.      Dissolve 1.20g thiamine hydrochloride (Vitamin B1) into 4.0mL water in a 125mL flask.


2.      When Vitamin B1 is dissolved, add 12.0mL 95% ethanol.

3.      Stopper the flask and cool the solution with a ice bath, slowly add 4.0mL of cold 2.5M sodium hydroxide to the flask, and make pH of the solution is about 10~11.

 Vitamin B1 solution turns into yellow after added sodium hydroxide soludtion


4.      Rapidly add ~6.24g benzaldehyde to the reaction mixture and sufficiently mix the solution. Stopper the flask and allow it to stand at room temperature for 24 hours.

 The appearance at the first

The appearance after 6 hours

The appearance after 9 hours

The appearance after 24 hours

5.      At the end of the reaction period, the benzoin should have separated as fine while crystals. 


6.      When the crystallization is completed, collect the crude product by filtration. And wash is with some cold water and ethanol.

The crude benzoin (still containing some Vitamin B1 and some NaOH)

7.      Recrystallize the product from 95% ethanol.



8.      Air dry the final product.

 The final product should be white crystals




Notes


1.      Vitamin B1 exists in the form of thiamine hydrochloride. It is stable in the acidic condition, but it absorbs water easily, and it is a heat-sensitive reagent, the thiamine in aqueous solution is oxidated easily by oxygen in the air. The rate of oxidation may be accelerated by light and some ions such as cupric ion, ironic ion and magnesium ion. It should be stored in a refrigerator. Since the thiazole ring is broken easily in basic solution, both the aqueous solutions of thiamine hydrochloride and sodium hydroxide should be cooled thoroughly with an ice bath before use.


2.      The control of the pH value is the key to the benzoin condensation of benzaldehyde. So the benzaldehyde used for this experiment must be free of benzoic acid. The benzaldehyde must be redistilled before use.



Experimental Record



Weight of benzaldehyde
6.11 g
Weight of benzoin after recrystallization and air dried
1.69 g
Yield
27.7 %













STEP 2


α-Diketones are very useful in the preparation of cyclic compounds of great value. Benzil, an α-diketone, is prepared by the oxidation of an α-hydroxyketone, benzoin. This oxidation can easily be done with mild oxidizing agent. In the experiment, the oxidation is performed with ironic chloride hexahydrate.



Reaction equation





Possible Mechanism



Step 1






Step 2







1H NMR


1H-NMR: Benzil300 MHz, CDCl3delta [ppm]mult.atomsassignment7.50m (d)4 H2-H, 2'-H, 6-H, 6'-H7.64m (dd)2 H4-H, 4'-H7.95m (dd)4 H3-H, 3'-H, 5-H, 5'-H
1H-NMR: Benzil
300 MHz, CDCl3
delta [ppm]mult.atomsassignment
7.50m (d)4 H2-H, 2'-H, 6-H, 6'-H
7.64m (dd)2 H4-H, 4'-H
7.95m (dd)4 H3-H, 3'-H, 5-H, 5'-H





13C NMR


13C-NMR: Benzil
75.5 MHz, CDCl3
delta [ppm]assignment
129.0CH arom.
129.8CH arom.
133.0CH arom.
154.8C quart. arom.
194.5C=O
76.5-77.5CDCl3



IR


IR: Benzil
[KBr, T%, cm-1]
[cm-1]assignment
3064arom. C-H valence
1660C=O valence, ketone
1594, 1579arom. C=C valence

GCpure product chromatogram


GC: pure productcolumnDB-1, L=28 m, d=0.32 mm, film=0.25 µminleton column injection, 0.2 µLcarrier gasH2, 40 cm/soven90°C (5 min), 10°C/min --> 240°C (30 min)detectorFID, 270°Cintegrationpercent concentration calculated from relative peak area



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Chemical


1.      Benzoin: 1.20g



2.      Ironic chloride hexahydrate: 5.10g


3.      Ethanol
4.      Acetic acid: ~6mL


Procedure

1.      Place 6mL of glacial acetic acid, 3mL of water, 5.1g FeCl3˙6H2O and a stir bar in a 100mL round-bottom flask fitted with a reflux condenser.

 I used a air condenser because the boiling point of the distillate is high
and it also safe more energy
  

2.      Heat gently the mixture to boil and shake the mixture occasionally. Stop heating and cool the solution slightly.


3.      Add 1.20g benzoin to the flask and continue to heat. Reflux the mixture 1 hour.
4.      Then add 30mL of water to the flask and heat the mixture again. After boil, cool the solution, yellow solid separates. Collect the crude product by filtration, and wash it three times with a small amount of cold water. 

 After add water

 Boil the solution again

 Place in an ice bath

5.      Recrystallize the crude product from 75% aqueous ethanol (about 30mL).



6.      Air dry the product and weight it.



 Get 0.80g


Experimental Record



Weight of benzoin added
1.20 g
Weight of benzil after recrystallization
0.80 g
Theory weight of benzil
1.19 g
Yield Rate
67.2 %







STEP 3


The sodium salt of 5,5-diphenylhygantion, Dilantin, is an anticonvulsant used for the treatment of epilepsy. 



The synthesis process of 5,5-diphenylhygantion is as follows:




Reaction equation:




Mechanism:






Chemical



1.      Benzil: 0.60 g



2.      Urea: 0.36 g


3.      Potassium hydroxide solution: ~2mL saturated(~14.8M)



4.      Sulfuric acid: 6M

5.      Ethanol 95%



Procedure



1.      Add 0.60g benzil and 0.36g urea in to a 50mL round-bottomed flask



2.      Add 6 mL 95% ethanol and 1~2mL KOH solution.



3.      Reflux the mixture with stirring for 2.5 hr.




4.      Cool the reaction mixture and remove the sparingly insoluble solid by gravity filtration.



5.      Cool the filtrate further in an ice-water bath and acidify the filtrate with 6M sulfuric (pH 1.5~3). The white powdered solid is obtained.



6.      Collect the product by filtration, and wash it thoroughly with water to remove the inorganic salt.



7.      Recrystallize the crude product from 95% ethanol.



8.      The white needle-shape crystal is obtained.




Experimental Record



Weight of benzil
0.60 g
Weight of final product (Dilantin)
0.36 g
Theoretical Weight of Dilantin
0.72 g
Yield
50.0 %


MASS SPECTRUM



1H NMR



1H NMR





13 C NMR



13 CNMR






IR SECTRUM
MASS SPECTRUM



OTHERS



Synthesis of benzil from benzoin using VOCl3



Benzoin ON VOCl3 OXIDN
SYNTHESIS............
http://kriemhild.uft.uni-bremen.de/nop/en/instructions/pdf/4002_en.pdf


Operating scheme



Equipment

Batch scale:0.01 mol0.1 molBenzoin

two-necked flask 250 mLtwo-necked flask 250 mLheatable magnetic stirrer with magnetic stir barheatable magnetic stirrer with magnetic stir bar
gas-filled balloongas-filled balloonadapter with ground-glass joint, ground-in stopcock and hose couplingadapter with ground-glass joint, ground-in stopcock and hose coupling
separating funnelseparating funnelrotary evaporatorrotary evaporator

Substances required

Batch scale:0.01 mol0.1 molBenzoin

EductsAmountRiskSafety
Benzoin
21.2 gRS
Oxygen
OO
82-17
CatalystAmountRiskSafety
Vanadium(V) oxychloride
TTCC
0.174 g14-25-348-26-28.1-30-36/37/39-45
SolventsAmountRiskSafety
Acetone
FFXiXi
100 mL11-36-66-672-9-16-26
Acetic acid ethyl ester
FFXiXi
250 mL11-36-66-672-16-26-33
Diethyl ether
F+F+XnXn
~5 mL12-19-22-66-672-9-16-29-33
OthersAmountRiskSafety
Sodium hydrogen carbonate
~30 gRS
Sodium chloride
XiXi
~60 g36/37/3824/25-26-36
Magnesium sulfate
RS
Solvents for analysisAmountRiskSafety
Petroleum ether (60-80)
FF
11-38-48/20-52/53-62-659-16-23.2-24-29-33-36/37-62
Methanol
FFTT
11-23/24/25-39/23/24/251/2-7-16-36/37-45
Dichloromethane
XnXn
402-23.1-24/25-36/37



Simple evaluation indices

Batch scale:0.01 mol0.1 molBenzoin

Atom economy92.1%
Yield59%
Target product mass12.3g
Sum of input masses330g
Mass efficiency38mg/g
Mass index26g input / g product
E factor25g waste / g product












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